CART (85-102)-Inhibition of psychostimulant-induced hyperlocomotion: Importance of cyclization

Synthetic derivative of C-terminal fragment of CART (55-102) with reduced thiol groups, [Abu86,94]CART (85-102)red, given together with amphetamine (5 mg/kg, s.c.) or cocaine (15 mg/kg, s.c.), reversed hyperlocomotion induced by these drugs at a dose of 0.1 μg but not at a higher dose. In the cerebral cortex homogenate, [Abu86,94]CART (85-102)red was nonspecifically cleaved from N- and C-termini. This peptide contains two chemically blocked Cys residues, and two others in reduced form. Concomitant with cleavage, rapid cyclization occurred. The newly formed cyclic peptides were stable. The cyclic peptide [Abu86,94]CART (85-102)ox failed to inhibit amphetamine- and cocaine-induced locomotor activity. The ability to inhibit the locomotor-stimulant activity of amphetamine was retained in [Abu86,88,94,101]CART (85-102), in which all Cys were replaced with 2-aminobutyric acid to prevent their pairing. Disulfide bridge formation may be an interesting mechanism that prevents proteolysis of [Abu86,94]CART (85-102)red and terminates its ability to reverse amphetamine-induced hyperlocomotion.